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1.
J Immunother ; 36(9): 490-5, 2013.
Article in English | MEDLINE | ID: mdl-24145360

ABSTRACT

Overexpression of vascular endothelial growth factor in renal cell carcinoma (RCC) leads to angiogenesis, tumor progression, and inhibition of immune function. We conducted the first phase II study to estimate the efficacy and safety of bevacizumab with high-dose interleukin-2 (IL-2) therapy in patients with metastatic RCC. Eligible patients had predominantly clear cell metastatic RCC, measurable disease, a Karnofsky Performance Status of ≥80%, and adequate end-organ function. IL-2 (600,000 IU/kg) was infused intravenously every 8 hours (maximum 28 doses) during two 5-day cycles on days 1 and 15 of each 84-day course. Bevacizumab (10 mg/kg) was infused intravenously every 2 weeks beginning 2 weeks before initiating IL-2. Fifty of 51 eligible patients from 8 centers were enrolled. Median progression-free survival (PFS) was 11.2 months (90% confidence interval, 5.7-17.7), and 2-year PFS was 18% (90% confidence interval, 8%-27%). Responses included 4 complete (8%) and 11 partial (22%) responses. Toxicities did not exceed those expected from each agent alone. Combining IL-2 plus bevacizumab is feasible, with a response rate and PFS at least as high as reported previously for the single agents. The regimen did not appear to enhance the rate of durable major responses over that of IL-2 alone.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Adult , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab , Carcinoma, Renal Cell/pathology , Dose-Response Relationship, Drug , Drug Administration Schedule , Fatigue/chemically induced , Female , Follow-Up Studies , Humans , Hypotension/chemically induced , Infusions, Intravenous , Interleukin-2/administration & dosage , Interleukin-2/adverse effects , Kaplan-Meier Estimate , Karnofsky Performance Status , Kidney Neoplasms/pathology , Lymphopenia/chemically induced , Male , Middle Aged , Neoplasm Metastasis , Treatment Outcome
2.
J Chemother ; 25(6): 362-8, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24093213

ABSTRACT

BACKGROUND: Temozolomide (TMZ) is an oral alkylating agent used in the treatment of central nervous system neoplasms and metastatic melanoma. Preclinical and clinical data suggested that combining TMZ with interferon alpha-2b (IFN-alpha-2b) may result in increased anti-tumour efficacy. METHODS: This was a phase I, dose-escalation study to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of cyclical oral TMZ (days 1-7 and 15-21) in combination with pegylated IFN-alpha-2b (PEG-IFN-alpha-2b) in patients with advanced solid tumours. RESULTS: We treated 19 patients (10 female and nine male), median age 58 years (range: 41-79 years). Ten patients tolerated TMZ at 100 mg/m² on days 1-7 and 15-21 plus PEG-IFN-alpha-2b at 1.5 mcg/kg/week on 28-day cycles which was the MTD of the combination. The pharmacokinetic parameters of PEG-IFN-alpha-2b were not altered by TMZ, at the MTD. CONCLUSION: The MTD of cyclical oral TMZ was 100 mg/m² on days 1-7 and 15-21 when combined with weekly subcutaneous PEG-IFNα-2b at 1.5 mcg/kg/week on 28 days cycles. The PK of PEG-IFN-alpha-2b appeared consistent with those when it is used as monotherapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Dacarbazine/administration & dosage , Dacarbazine/adverse effects , Dacarbazine/analogs & derivatives , Dacarbazine/pharmacokinetics , Female , Humans , Interferon alpha-2 , Interferon-alpha/administration & dosage , Interferon-alpha/adverse effects , Interferon-alpha/pharmacokinetics , Male , Maximum Tolerated Dose , Middle Aged , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/adverse effects , Polyethylene Glycols/pharmacokinetics , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Recombinant Proteins/pharmacokinetics , Temozolomide , Treatment Outcome
3.
Invest New Drugs ; 31(4): 937-42, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23315028

ABSTRACT

PURPOSE: Preclinical studies in human melanoma cell lines and murine xenograft tumor models suggest that the proteasome inhibitor bortezomib enhances the activity of the cytotoxic agent dacarbazine. We performed a phase I trial of bortezomib and dacarbazine in melanoma, soft tissue sarcoma, and amine precursor uptake and decarboxylation tumors. The primary objective was to identify recommended phase II doses for the combination. EXPERIMENTAL DESIGN: Bortezomib and dacarbazine were both administered intravenously once weekly. All patients received prophylactic antiemetics. Dose escalation proceeded using a standard 3 + 3 design. Response was assessed according to NCI RECIST v1.0. RESULTS: Twenty eight patients were enrolled to six dose levels. Bortezomib 1.6 mg/m(2) and dacarbazine 580 mg/m(2) are the recommended phase II weekly doses. The combination was generally well tolerated. Among 15 patients with melanoma there was one durable complete response in a patient with an exon-11 cKIT mutation, and one partial response. Among 12 patients with soft tissue sarcoma there was one partial response. CONCLUSIONS: Bortezomib 1.6 mg/m(2) and dacarbazine 580 mg/m(2) administered intravenously once weekly is well tolerated and has at least minimal activity in melanoma and soft tissue sarcoma.


Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Boronic Acids/therapeutic use , Dacarbazine/therapeutic use , Melanoma/drug therapy , Pyrazines/therapeutic use , Sarcoma/drug therapy , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Boronic Acids/adverse effects , Bortezomib , Dacarbazine/adverse effects , Dose-Response Relationship, Drug , Female , Humans , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/secondary , Male , Medication Adherence , Melanoma/diagnostic imaging , Middle Aged , Pyrazines/adverse effects , Radiography , Treatment Outcome , Young Adult
4.
PLoS One ; 7(10): e46600, 2012.
Article in English | MEDLINE | ID: mdl-23118856

ABSTRACT

PURPOSE: To evaluate CD4(+)CD25(+)FOXP3(+) T regulatory cells (T(REG)) and associated immune-regulatory pathways in peripheral blood lymphocytes (PBL) of metastatic renal cell carcinoma (mRCC) patients and healthy volunteers. We subsequently investigated the effects of immunotherapy on circulating T(REG) combining an extensive phenotype examination, DNA methylation analysis and global transcriptome analysis. DESIGN: Eighteen patients with mRCC and twelve volunteers (controls) were available for analysis. T(REG) phenotype was examined using flow cytometry (FCM). T(REG) were also quantified by analyzing the epigenetic status of the FOXP3 locus using methylation specific PCR. As a third approach, RNA of the PBL was hybridized to Affymetrix GeneChip Human Gene 1.0 ST Arrays and the gene signatures were explored using pathway analysis. RESULTS: We observed higher numbers of T(REG) in pre-treatment PBL of mRCC patients compared to controls. A significant increase in T(REG) was detected in all mRCC patients after the two cycles of immunotherapy. The expansion of T(REG) was significantly higher in non-responders than in responding patients. Methylation specific PCR confirmed the FCM data and circumvented the variability and subjectivity of the FCM method. Gene Set Enrichment Analysis (GSEA) of the microarray data showed significant enrichment of FOXP3 target genes, CTLA-4 and TGF-ß associated pathways in the patient cohort. CONCLUSION: Immune monitoring of the peripheral blood and tumor tissue is important for a wide range of diseases and treatment strategies. Adoption of methodology for quantifying T(REG) with the least variability and subjectivity will enhance the ability to compare and interpret findings across studies.


Subject(s)
Carcinoma, Renal Cell , Forkhead Transcription Factors , Immunotherapy , Metabolic Networks and Pathways/immunology , T-Lymphocytes, Regulatory , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , CTLA-4 Antigen/genetics , CTLA-4 Antigen/metabolism , Carcinoma, Renal Cell/blood , Carcinoma, Renal Cell/immunology , Cell Proliferation , DNA Methylation , Female , Flow Cytometry , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/immunology , Forkhead Transcription Factors/metabolism , Gene Expression Profiling , Humans , Interleukin-2/administration & dosage , Male , Neoplasm Metastasis , Neoplastic Cells, Circulating/pathology , Oligonucleotide Array Sequence Analysis , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Transforming Growth Factor beta/immunology , Transforming Growth Factor beta/metabolism , Vaccination
5.
J Clin Oncol ; 28(7): 1196-202, 2010 Mar 01.
Article in English | MEDLINE | ID: mdl-20124177

ABSTRACT

PURPOSE: Recovery of lymphocyte populations after lymphocyte depletion is implicated in therapeutic immune pathways in animal models and in patients with cancer. We sought to evaluate the effects of chemotherapy-induced lymphodepletion followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) and high-dose interleukin-2 (IL-2) therapy on clinical response and the recovery of lymphocyte subcompartments in patients with metastatic melanoma. PATIENTS AND METHODS: This was a two-stage phase II trial design. Patients with measurable metastatic melanoma were treated with intravenous cyclophosphamide (60 mg/kg, days 1 and 2) and fludarabine (25 mg/m(2), day 3 through 7) followed by two 5-day courses of intravenous high-dose bolus IL-2 (600,000 U/kg; days 8 through 12 and 21 through 25). GM-CSF (250 microg/m(2)/d beginning day 8) was given until granulocyte recovery. Lymphocyte recovery profiles were determined by flow cytometric phenotyping at regular intervals, and clinical outcome was assessed by Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: The trial was stopped at the end of stage 1 with four of 18 objective responses noted. Twelve patients had detailed lymphocyte subcompartments evaluated. After lymphodepletion, we observed an induction of regulatory cells (CD4+ T regulatory cells; CD8+ T suppressor cells) and of T memory cells (CD8+ T central memory cells; T effector memory RA+ cells). Expansion of circulating melanoma-specific CD8(+) cells was observed in one of four HLA-A2-positive patients. CONCLUSION: Chemotherapy-induced lymphodepletion modulates the homeostatic repopulation of the lymphocyte compartment and influences recovering lymphocyte subpopulations. Clinical activity seems similar to standard high-dose aldesleukin alone.


Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor/administration & dosage , Interleukin-2/administration & dosage , Lymphocyte Depletion , Melanoma/drug therapy , Adult , Aged , CD4 Lymphocyte Count , CD8-Positive T-Lymphocytes/immunology , Female , Granulocyte-Macrophage Colony-Stimulating Factor/adverse effects , Humans , Interleukin-2/adverse effects , Male , Melanoma/immunology , Melanoma/secondary , Middle Aged , T-Lymphocytes, Regulatory/immunology
6.
Clin Cancer Res ; 15(15): 4986-92, 2009 Aug 01.
Article in English | MEDLINE | ID: mdl-19622576

ABSTRACT

PURPOSE: To evaluate the clinical and immunologic outcomes of DC (dendritic cell) vaccine with interleukin (IL)-2 and IFN-alpha 2a in metastatic renal cell carcinoma patients. EXPERIMENTAL DESIGN: Eighteen consented and eligible patients were treated. Peripheral blood monocytes were cultured ex vivo into mature DCs and loaded with autologous tumor lysate. Treatment consisted of five cycles of intranodal vaccination of DCs (1 x 10(7) cells/1 mL Lactated Ringer's solution), 5-day continuous i.v. infusion of IL-2 (18MiU/m2), and three s.c. injections of IFN-alpha 2a (6MiU) every other day. Response Evaluation Criteria in Solid Tumors criteria were used for disease assessment. Correlative immunologic end points included peripheral blood lymphocyte cell phenotype and function as well as peripheral blood anti-renal cell carcinoma antibody and cytokine levels. RESULTS: All patients received between two and five treatment cycles. Toxicities consisted of known and expected cytokine side effects. Overall objective clinical response rate was 50% with three complete responses. Median time to progression for all patients was 8 months, and median survival has not been reached (median follow up of 37+ months). Treatment-related changes in correlative immunologic end points were noted and the level of circulating CD4(+) T regulatory cells had a strong association with outcome. Pre-IP-10 serum levels approached significance for predicting outcome. CONCLUSIONS: The clinical and immunologic responses observed in this trial suggest an interaction between DC vaccination and cytokine therapy. Our data support the hypothesis that modulation of inflammatory, regulatory, and angiogenic pathways are necessary to optimize therapeutic benefit in renal cell carcinoma patients. Further exploration of this approach is warranted.


Subject(s)
Antineoplastic Agents/administration & dosage , Cancer Vaccines/administration & dosage , Carcinoma, Renal Cell/therapy , Dendritic Cells/immunology , Interferon-alpha/administration & dosage , Interleukin-2/analogs & derivatives , Kidney Neoplasms/therapy , Adult , Aged , CD8-Positive T-Lymphocytes/immunology , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/secondary , Chemokine CXCL10/blood , Cytokines/blood , Female , Humans , Immunotherapy/methods , Interferon alpha-2 , Interleukin-2/administration & dosage , Kidney Neoplasms/immunology , Kidney Neoplasms/pathology , Lymph Nodes/immunology , Male , Middle Aged , Recombinant Proteins/administration & dosage , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism
7.
J Clin Oncol ; 26(14): 2292-8, 2008 May 10.
Article in English | MEDLINE | ID: mdl-18467720

ABSTRACT

PURPOSE: High-dose interleukin-2 (IL-2) induces responses in 15% to 20% of patients with advanced melanoma; 5% to 8% are durable complete responses (CRs). The HLA-A2-restricted, modified gp100 peptide (210M) induces T-cell immunity in vivo and has little antitumor activity but, combined with high-dose IL-2, reportedly has a 42% (13 of 31 patients) response rate (RR). We evaluated 210M with one of three different IL-2 schedules to determine whether a basis exists for a phase III trial. PATIENTS AND METHODS: In three separate phase II trials, patients with melanoma received 210M subcutaneously during weeks 1, 4, 7, and 10 and standard high-dose IL-2 during weeks 1 and 3 (trial 1), weeks 7 and 9 (trial 2), or weeks 1, 4, 7, and 10 (trial 3). Immune assays were performed on peripheral-blood mononuclear cells collected before and after treatment. RESULTS: From 1998 to 2003, 131 patients with HLA-A2-positive were enrolled. With 60-month median follow-up time, the overall RR for 121 assessable patients was 16.5% (95% CI, 10% to 26%); the RRs were 23.8% in trial 1 (42 patients), 12.5% in trial 2 (40 patients), and 12.8% in trial 3 (39 patients). There were 11 CRs (9%) and nine partial responses (7%), with 11 patients (9%) progression free at >or= 30 months. Immune studies including assays of CD3-zeta expression and numbers of CD4(+)/CD25(+)/FoxP3(+) regulatory T cells, CD15(+)/CD11b(+)/CD14(-) immature myeloid-derived cells, and CD8(+)gp100 tetramer-positive cells in the blood did not correlate with clinical benefit. CONCLUSION: The results again demonstrate efficacy of high-dose IL-2 in advanced melanoma but did not demonstrate the promising clinical activity reported with vaccine and high-dose IL-2 in any of three phase II trials.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , HLA-A2 Antigen/biosynthesis , Melanoma/immunology , Melanoma/therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cancer Vaccines/administration & dosage , Combined Modality Therapy , Dose-Response Relationship, Drug , Female , Freund's Adjuvant/administration & dosage , HLA-A2 Antigen/immunology , Humans , Interleukin-2/administration & dosage , Interleukin-2/adverse effects , Male , Mannitol/administration & dosage , Mannitol/analogs & derivatives , Melanoma/drug therapy , Membrane Glycoproteins/administration & dosage , Membrane Glycoproteins/adverse effects , Middle Aged , Oleic Acids/administration & dosage , gp100 Melanoma Antigen
8.
Clin Cancer Res ; 13(2 Pt 2): 733s-740s, 2007 Jan 15.
Article in English | MEDLINE | ID: mdl-17255302

ABSTRACT

In patients with progressive malignancy, the natural balance between proinflammatory (Yang) and inhibitory (regulatory or Yin) immune pathways is disrupted and favors cancer-specific immune suppression. Therapy with interleukin 2 (IL-2) can mobilize immune effector cells that recognize and destroy cancer. High-dose IL-2 is the only therapy that has consistently induced complete durable remissions in patients with metastatic renal cell carcinoma (RCC) but only in a few of them. The lack of benefit in most metastatic RCC patients is likely due to the ineffective manipulation of other immune circuits critical in regulating tumor cytotoxic pathways. The limited clinical activity of IL-2, RCC vaccines, and other immune therapies to date leads us to postulate that effective clinical treatment strategies will need to simultaneously enhance proinflammatory pathways and disrupt regulatory pathways. We present preliminary studies in RCC patients to highlight the complexity of the regulatory pathways and our approach to shifting the balance of proinflammatory and regulatory immune pathways using dendritic cell-tumor lysate vaccine followed by cytokine therapy.


Subject(s)
Cancer Vaccines/pharmacology , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/therapy , Cytokines/therapeutic use , Dendritic Cells/metabolism , Humans , Immune System , Inflammation , Interleukin-2/metabolism , Interleukin-2/therapeutic use , Kidney Neoplasms/therapy , Neoplasm Metastasis , Time Factors , Treatment Outcome
9.
J Urol ; 171(3): 1036-42, 2004 Mar.
Article in English | MEDLINE | ID: mdl-14767265

ABSTRACT

PURPOSE: Biological therapy for renal cell carcinoma (RCC) uses agents that mobilize immune effector cells which are able to recognize and destroy cancer. We evaluated the effects of weekly then monthly autologous tumor vaccine combined with daily granulocyte macrophage-colony stimulating factor (GM-CSF) in patients with RCC as a method of stimulating antigen presenting cells. MATERIALS AND METHODS: Eligible patients with pathological stage II to IV RCC were entered into this pilot study. Autologous tumor vaccine (0.5 to 1 x 107 irradiated tumor cells) admixed with 250 microg GM-CSF per vaccine was given subcutaneously weekly for 4 weeks and then monthly for 4 months. GM-CSF (125 microg/m2) was given subcutaneously for 13 days after vaccine injection 1 and injections 4 to 8. Treatment related tumor specific CD4 and CD8 positive T cell precursors were assessed. RESULTS: A total of 22 patients were entered into this study. Patients were stratified by bulk of disease (group 1, 9 patients with micrometastatic disease, and group 2, 13 patients with macrometastatic disease). In general treatment was well tolerated. Of 9 patients in group 1 7 remained disease-free after nephrectomy. In group 2, 6 patients had stable (46.2%) and 7 patients had progressive disease (53.8%). Statistically significant treatment related increases in CD4 (p = 0.028) and CD8 (p = 0.018) positive tumor specific T cell precursors were observed for the entire group of patients. Changes in CD4 and CD8 positive precursors correlated significantly with each other (p = 0.0001). This correlation was seen in the 2 patient subpopulations as well (group 1 p = 0.003, group 2 p = 0.013). Patients with minimal disease, and with changes in CD4 and CD8 positive tumor specific T cell precursors greater than the median appeared to have an improved time to progression as well as a survival benefit. CONCLUSIONS: GM-CSF and autologous vaccine can be given safely in combination to patients with renal cell cancer. We observed treatment related changes in tumor specific circulating lymphocyte populations.


Subject(s)
Cancer Vaccines/therapeutic use , Carcinoma, Renal Cell/drug therapy , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Kidney Neoplasms/drug therapy , Adult , Aged , Carcinoma, Renal Cell/immunology , Follow-Up Studies , Humans , Kidney Neoplasms/immunology , Middle Aged , Pilot Projects
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